Valproic acid (Chemical Abstracts Service (CAS) Registry No. 99-66-1) is a branched carboxylic acid having the molecular formula C8H16O2. Valproic acid is also known as 2-propylpentanoic acid, 2-propylvaleric acid, and dipropylacetic acid. Valproic acid is a colorless liquid having a boiling point of 120-121° C. at 14 torr. The compound is very slightly soluble in water. It has a pKa of 4.6, and reacts with bases to form salts generally known as valproates.
Clinical Uses
Valproic acid (valproate) has been approved by regulatory agencies around the world, including the U.S. Food and Drug Administration (FDA), as a therapy for several clinical indications, including neurological disorders, mania, manic episodes associated with bipolar disorder, epilepsy, and affective and attention deficit disorders. In addition, valproate is used for the prophylactic treatment, modulation and management of migraine headache, chronic pain, and neuropathic pain.
Further, potential therapeutic benefits of valproate in still other clinical indications are being evaluated in on-going clinical trials. Valproate therapy is being evaluated in clinical studies assessing activity of the substance as a histone deacetylase inhibitor to promote cell differentiation and regeneration, or to regulate gene expression in subjects afflicted with spinal muscular atrophy. Likewise, valproate may exhibit therapeutic benefit as a combinatorial therapeutic treatment of human cancers and for the treatment of tumor metastasis. Similarly, valproate may be useful in the treatment and management of pain, for treating severe tinnitus, for treatment of disorders of personal attachment and deficient social interaction, or for treating Alzheimer's disease. Pre-clinical studies also show that valproate may promote neural stem cell differentiation and or be useful as a co-medicament to promote the elimination of the Human Immunodeficiency Virus (HIV) or other retroviruses from the body or to prevent progression of a retroviral infection to AIDS.
Sources of the Active Pharmaceutical Ingredient Valproate
Although valproate is a therapeutically active pharmaceutical ingredient, valproic acid is an oil that is difficult to formulate and use in the preparation of dosage forms suitable for human or veterinary use. In addition, the administration of valproic acid to subjects requiring its therapeutic administration results in the exhibition of deleterious side effects, including gastrointestinal distress and ulceration. Pharmaceutical and pharmacological advantages are gained when therapeutic dosage forms are prepared from alkali metal or alkaline earth metal salts of valproic acid. Therefore, alkali metal or alkaline earth metal salts of valproic acid are used in present-day clinical formulations as sources of the active drug ingredient, valproate.
Sodium (Na1+), calcium (Ca2+) and magnesium (Mg2+) valproates have been evaluated for use in pharmaceutical and veterinary compositions. Sodium valproate is a hygroscopic salt that is difficult to formulate into pharmaceutical formulations. In contrast, non-stoichiometric valproate sodium compounds comprising combinations of sodium valproate and valproic acid (divalproex sodium, for example) are not hygroscopic, and are bioavailable and therapeutically active sources of valproate. (The non-stoichiometric compound known as divalproex sodium is disclosed in U.S. Pat. No. 4,988,731, for example, and one of its therapeutic embodiments is described in the FDA Approved Labeling Text for NDA 21-168, Aug. 4, 2000.) At the present time, divalproex sodium is the most commonly formulated source of the drug valproate.
Calcium valproate has also been evaluated for use in pharmaceutical and veterinary formulations. Methods for the preparation of calcium salts of valproic acid are disclosed in U.S. Pat. No. 4,895,873. Although pharmaceutical formulations comprising calcium valproate have been approved by the regulatory bodies of several countries, the use of this valproate salt has been severely restricted following publication of reports of adverse toxicological and reproductive effects in dogs, rats, mice, rabbits, and rats. (For example, adverse effects caused by calcium valproate administration are reported in “Calcium valproate-induced uterine adenocarcinomas in Wistar rats” by Watkins, Gough, et al. in Toxicology, Vol. 41, pages 35-47, 1993.)
Magnesium valproate is also used in clinical formulations. Magnesium valproate, which has the CAS Registry No. 6285-943-7, a molecular formula of C16H30O4Mg, and a molecular weight of 310.71, is also known as magnesium 2-propylvalerate and as 2-propylpentanoic acid magnesium salt. By weight, its composition is 61.8% carbon, 9.7% hydrogen, 7.8% magnesium, and 20.6% oxygen.
Clinical investigators have reported that magnesium valproate possesses pharmacokinetic properties comparable to sodium valproate or valproic acid, is hydrolyzed to valproic acid and magnesium ions upon absorption in the bloodstream, and has important advantages in comparison with either sodium valproate or valproic acid. Among the therapeutic advantages of magnesium valproate are the clinical observations that magnesium valproate exhibits a slower and more regular absorption rate, which prevents the variations in plasma levels of valproate typically observed when sodium salts of valproic acid are administered. Additional therapeutic benefits are afforded by magnesium ions, which possess anticonvulsant and sedative properties. [X. Rabasseda, Drugs of Today, Vol. 31, No. 3, 1995, pp. 185-190.] In contrast to calcium valproate, which exacerbates malignancy, magnesium valproate is a useful therapy when administered to patients with cervical cancer. For example, Chavez-Blanco et al. have reported that magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues. [A. Chavez-Blanco, B. Segura-Pacheco, et al., Molecular Cancer Jul. 7, 2005, Vol. 4, pp. 22ff.]
In spite of the therapeutic benefits of magnesium valproate, this valproate salt is used less frequently than other valproates in pharmaceutical and veterinary formulations. One reason is the difficulty in preparing the magnesium salt having the formula C16H30O4Mg with physicochemical properties suited to pharmaceutical applications. The known methods for its preparation suffer from deficiencies in pharmaceutical manufacturing utility and provide magnesium valproate lacking the purity, solubility, and physicochemical properties which enable its use in pharmaceutical formulations for human clinical or veterinary use.
Spanish Patent No. ES 430062 discloses one method for the preparation of magnesium valproate in which valproic acid is allowed to react with magnesium oxide in alcoholic medium. The method has the following shortcomings. The reaction is carried out in a suspension. Reaction times are lengthy. The final product is contaminated with unreacted magnesium oxide, which commingles with the desired product when acetone is added to precipitate the magnesium valproate. The resulting product is an amorphous solid that is difficult to purify and dry. The product has poor bioavailability.
In U.S. Pat. No. 5,180,850 to Cavazza, a method is disclosed for the preparation of crystalline magnesium valproate. (The same procedure is disclosed in Italian Patent No. 2,283,789 and in EP 433,848 B1.) According to the method of Cavazza, valproic acid is reacted with a substantially stoichiometric amount of a magnesium alkoxide selected from magnesium ethoxide, magnesium propoxide, and magnesium isopropoxide in methanol or ethanol. The magnesium salt of valproic acid is isolated in a microcrystalline form by solvent evaporation or by acetone precipitation. The method has the following shortcomings. Product isolation by solvent evaporation provides product that is contaminated by incompletely reacted starting materials or adventitious contaminants in starting materials or solvents. When the reaction is carried out in ethanol, the quantity of magnesium ethoxide specified is not completely dissolved in the volume of ethanol taught. Although some conversion to magnesium valproate occurs, the method does not permit control of temperature, reaction time, removal of impurities, etc. When the reaction is carried out in methanol, the addition of acetone fails to precipitate the product, using the volume of acetone taught in the patent.
In U.S. Pat. No. 6,753,349, Weh discloses a method for producing compositions containing at least one molecule of a valproic acid salt and at least one molecule of valproic acid. The valproic acid salt represents an alkali or alkaline earth salt of valproic acid, wherein the alkali salt is a valproate salt of lithium, sodium, potassium, or rubidium, and the alkaline earth salt of valproic acid is a valproate salt of magnesium, calcium, strontium, or barium. Preferably, the valproate salt is a sodium, potassium, magnesium or calcium salt. The compounds of Weh's invention have the general formula:[(CH3CH2CH2)2CH—C(O)O Me]m[(CH3CH2CH2)2CH—C(O)OH]n.x H2Oin which Me is Li1+, Na1+, K1+, Rb1+, Mg2+, Ca2+, Sr2+, or Ba2+, preferably Na1+, K1+, Mg2+, or Ca2+; m is an integer from 1 to 10, preferably from 1 to 6, n is an integer from 1 to 9, preferably from 1 to 3, and the ratio m:n is from 1:1 to 6:1, preferably 1:1 to 5:3 and particularly preferably 1:1, 4:3, or 2:1; and x is zero, 1 or 2, preferably zero or 1. In general, the method of preparing magnesium valproate compositions of Weh's invention comprises combining a selected amount of magnesium carbonate, magnesium bicarbonate, or combinations thereof with a selected amount of valproic acid to form a reaction mixture; and allowing the valproic acid to react directly with the magnesium carbonate, magnesium bicarbonate, or combinations thereof under conditions where the reaction temperature is controlled above the melting point of valproic acid. The methods exhibit the following shortcomings. Neither U.S. Pat. No. 6,753,349 nor related international patents WO 2001/032595 and EP 1,230,205 B1 disclose methods for the preparation of each of the several magnesium valproate compositions that are disclosed in these patents. In the absence of data disclosing the ratios of magnesium carbonate and/or magnesium bicarbonate that must be employed to obtain one of the several magnesium valproate compositions that are disclosed by Weh, a knowledgeable artisan must undertake extensive experiments in order to define a process suitable for pharmaceutical manufacturing. Further, valproic acid is an oil and not a solid with a known melting point, so omission in the disclosure of an optimal reaction temperature also requires extensive experimentation. The final product is contaminated with unreacted magnesium carbonate or bicarbonate, as well as other magnesium valproate salts, all of which commingle with the desired product. No methods for product purification are disclosed. The bioavailability of Weh's magnesium valproate compositions is not reported.
In brief, clinicians have shown that magnesium valproate is a useful source of the drug valproate that provides therapeutic benefits and an absence of adverse effects commensurate with or exceeding those observed when valproic acid, sodium valproate compositions, and other valproate salts are used as a source of valproate. To date, however, significant shortcomings in preparative methods have prevented broader therapeutic applications of magnesium valproate. The present invention remedies these shortcomings.